Cytoplasmic MSH2 immunoreactivity in a patient with Lynch syndrome with anEPCAM-MSH2fusion

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Immunohistochemistry for mismatch repair (MMR) proteins is being increasingly used to examine MMR status in tumours. The aim of the present article was to report the case of a colon cancer patient with Lynch syndrome who showed unusual cytoplasmic MMR protein localization.

Methods and results:

Histologically, the colon cancer was diagnosed as medullary carcinoma associated with prominent tumour-infiltrating lymphocytes and a Crohn's-like reaction. Immunohistochemistry revealed cytoplasmic and nuclear expression of MSH2 in non-neoplastic cells, and exclusively cytoplasmic expression in tumour cells. MSH6 expression was nuclear in non-neoplastic cells, but was lost in tumour cells. Nuclear expression of MLH1 and PMS2 was retained in both non-neoplastic and tumour cells. The tumour was microsatellite instability-high, which is indicative of defective MMR function. A subsequent germline mutation analysis identified a genomic deletion spanning the 3′ region of EPCAM and the 5′ region of MSH2, resulting in an in-frame fusion of EPCAM and MSH2.


The unusual cytoplasmic immunoreactivity of MSH2 was considered to be attributable to the non-functional EPCAM-MSH2 fusion product. The present case illustrates that not only loss of expression, but also abnormal localization, of MMR proteins is indicative of a defective MMR system.

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